Tomasi Thomas B, Magner William J, Khan A Nazmul H
Department of Immunology, Laboratory of Molecular Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Immunol Immunother. 2006 Oct;55(10):1159-84. doi: 10.1007/s00262-006-0164-4. Epub 2006 May 6.
According to the concept of immune surveillance, the appearance of a tumor indicates that it has earlier evaded host defenses and subsequently must have escaped immunity to evolve into a full-blown cancer. Tumor escape mechanisms have focused mainly on mutations of immune and apoptotic pathway genes. However, data obtained over the past few years suggest that epigenetic silencing in cancer may be as frequent a cause of gene inactivation as are mutations. Here, we discuss the evidence that tumor immune evasion is mediated by non-mutational epigenetic events involving chromatin and that epigenetics collaborates with mutations in determining tumor progression. Since epigenetic changes are potentially reversible, the relative contribution of mutations and epigenetics, to the gene defects in any given tumor, may be a factor in determining the efficacy of treatments. We review new developments in basic chromatin mechanisms and in this context describe the rationale for the current use of epigenetic agents in cancer therapy and for a novel epigenetically generated tumor vaccine model. We emphasize that epigenetic cancer treatments are currently a 'blunt-sword' and suggest future directions for designing chromatin-based programs of potential value in the diagnosis and treatment of cancer.
根据免疫监视的概念，肿瘤的出现表明其早期已逃避宿主防御，随后必定逃脱了免疫监视，进而发展为成熟的癌症。肿瘤逃逸机制主要集中在免疫和凋亡通路基因的突变上。然而，过去几年获得的数据表明，癌症中的表观遗传沉默可能与突变一样，是导致基因失活的常见原因。在此，我们讨论肿瘤免疫逃逸由涉及染色质的非突变表观遗传事件介导的证据，以及表观遗传学在决定肿瘤进展过程中与突变协同作用的证据。由于表观遗传变化可能是可逆的，在任何给定肿瘤中，突变和表观遗传学对基因缺陷的相对贡献可能是决定治疗效果的一个因素。我们回顾了基础染色质机制的新进展，并在此背景下描述了目前在癌症治疗中使用表观遗传药物的原理以及一种新型表观遗传产生的肿瘤疫苗模型的原理。我们强调，目前表观遗传癌症治疗是一把“双刃剑”，并提出了未来设计基于染色质的方案的方向，这些方案在癌症诊断和治疗中具有潜在价值。
